Amyloidosis is a series of diseases where proteins forming a fiber structure are deposited in the whole-body organs to induce functional disturbance and includes various diseases such as Alzheimer dementia and prion disease (Non-patent reference 1).
Familial Amyloidotic Polyneuropathy (FAP) is autosomal dominant, hereditary, systemic amyloidosis caused by point mutation or deletion of genes of TTR, apolipoprotein A1, gelsolin and the like (Non-patent reference 2). Among these, FAP caused by genetic mutation of TTR is most common. It is known that mutant TTRs form amyloid fibril which is normally deposited in almost all the tissues of the whole body such as the peripheral nerve, the heart, the kidney, the digestive tract, the eye, the brain and the meninges after middle age. It is an intractable disease which shows very bad convalescence of patients and is mortal within around 10 years after onset of disease.
Up till the present, more than 100 point mutations and deletions of TTR gene have been reported. In particular, Va130Met mutation (hereinafter referred to as “V30M”), in which the 30th valine in TTR is mutated to methionine, is most common. There are many patients in Portugal, Sweden and Japan. Since more than 6,000 cases of FAP patients have been confirmed in Portugal, there are not a small number of regions where FAP has not yet been investigated and it is expected that worldwide discovery of FAP patients will continue, it is supposed that there are well over 10,000 patients all over the world. It became known from the recent research that the clinical picture (age of onset, deposit organ specificity, etc.) of FAP is greatly affected by the kind of mutation of TTR gene (Non-patent reference 3). For instance, with regard to age of onset of FAP, L55P mutation shows fulminant clinical picture that the disease develops in one's teens whereas with V122I mutation the disease develops at sixty and thereafter. On the other hand, it is known that V30M mutation shows both types of disease where the disease develops at a younger age and at an older age. With regard to deposit organ specificity, D18G mutation causes deposition at the brain and the meninges to cause central nerves disturbance whereas V30M mutation causes deposition in the whole-body tissues to cause peripheral nerves disturbance and myocardial disturbance (Non-patent references 3 and 4).
TTR is a protein that consists of 127 amino acid residues with a molecular weight of 14 kDa and has a structure that eight β-strands present inside form two antiparallel β-sheets (Non-patent reference 5). TTR is produced predominantly in the liver but also in the ventricular choroid plexus, the retinal pigment epithelium cells of retina, the spleen, and the like. TTR usually forms a stable structure by forming a tetramer with a molecular weight of 55 kDa in blood and functions as a carrier of a vitamin A/retinol-binding protein complex and thyroid hormone T4 mainly in blood and cerebrospinal fluid. Its blood level is as high as 200-400 μg/mL but its half-life is as short as 2 days (Non-patent references 2-6). It is known that in the center of a TTR tetramer are present two homologous T4-binding sites to which T4 binds to stabilize the tetramer structure (Non-patent reference 3). There are various reports about another function of TTR such as the insulin secretion promoting activity, the cerebral nerve protecting activity, and the activity relating to lipid metabolism (Non-patent reference 2). On the other, although a blood level of retinol and thyroid hormone decreases in TTR gene knockout mice, no significant change in phenotypes such as a survival rate and fertility property could be seen (Non-patent reference 7) and thus it remains unknown whether TTR is directly essential for maintenance of actual biological activity.
For amyloidogenesis by TTR, dissociation from a tetramer to a monomer and structural change of a monomer are very important steps (Non-patent reference 3). Among these, it has been revealed that dissociation from a tetramer to a monomer is a rate-determining step of the reaction. On the other hand, in the course where TTR forms amyloid that deposits in the tissues and damages the whole-body organs, a molecular form that exerts toxicity to the tissues has not yet been fully elucidated. It is reported that a monomer and a low molecular weight oligomer such as a dimer exhibit cytotoxicity whereas TTR amyloid of 100 kDa or more dose not (Non-patent reference 5) and so it is to be hoped that future research will clarify relationship between toxicity and a molecular form.
Therapeutic strategy for FAP originating from genetic anomaly of TTR is chiefly classified into the following four groups.    (1) To suppress a produced level of variant TTRs    (2) To stabilize a TTR tetrameric structure containing variant TTRs    (3) To prevent amyloid formation of TTR dissociated from a tetramer    (4) To remove TTR amyloid deposited in tissues
Since almost all TTRs in blood are produced in the liver (Non-patent reference 2), the most common therapy at present is liver transplantation as classified in (1) above. Although delay in progression of the disease is observed by liver transplantation, it is inevitable to use an immunosuppressant through life with a great burden to donors and patients. Besides, deposition still continues in several organs including the eyes and the heart and thus exacerbation of symptoms in these organs can be seen in not a few cases (Non-patent reference 8). As such, it is problematic and hence development of an effective therapeutic method is earnestly desired.
For other therapeutic methods than liver transplantation, therapeutic methods using siRNA or an antisense oligonucleotide is at a stage of clinical development in case of the strategy (1). However, with all these methods, production of not only variant TTRs but also wild-type TTR is suppressed and thus their safety assessment when used for a long period of time should carefully be done. As for the strategy (2), a medicament has been developed that binds to the T4-binding sites of a TTR tetramer to thereby stabilize the tetrameric structure. The new medicine Vyndaqel® developed in accordance with the strategy has been approved in EU in 2011 and in Japan in 2013. As the result of clinical test for as long as 30 months, Vyndaqel® exhibited the effect to delay peripheral neuropathy in FAP patients but failed to suppress completely the progress of symptoms (Non-patent reference 9). Also for the strategies (3) and (4), although plural kinds of medicaments are at a stage of clinical development, the status quo is that none of the therapies can be a radical treatment.